tbuckley/cabot-search huggingface dataset:
Waning effectiveness of BNT162b2 and ChAdOx1 covid-19 vaccines over six months since second dose: OpenSAFELY cohort study using linked electronic health records
Authors: Elsie M F Horne, William J Hulme, Ruth H Keogh, Tom M Palmer, Elizabeth J Williamson, Edward P K Parker, Amelia Green, Venexia Walker, Alex J Walker, Helen Curtis, Louis Fisher, Brian MacKenna, Richard Croker, Lisa Hopcroft, Robin Y Park, Jon Massey, Jessica Morley, Amir Mehrkar, Sebastian Bacon, David Evans, Peter Inglesby, Caroline E Morton, George Hickman, Simon Davy, Tom Ward, Iain Dillingham, Ben Goldacre, Miguel A Hernán, Jonathan A C Sterne
Journal: BMJ (2022)

To estimate waning of covid-19 vaccine effectiveness over six months after second dose.
Symptoms of Mental Health Conditions and Suicidal Ideation Among State, Tribal, Local, and Territorial Public Health Workers — United States, March 14–25, 2022
Authors: Ahoua Koné, Libby Horter, Isabel Thomas, Ramona Byrkit, Barbara Lopes-Cardozo, Carol Y. Rao, Charles Rose
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

An increase in adverse mental health symptoms occurred in the general population at the onset of the COVID-19 pandemic, which peaked in 2020 and subsequently decreased (1-3). The pandemic exacerbated existing stress and fatigue among public health workers responding to the public health crisis.* During March-April 2021, a survey of state, tribal, local, and territorial (STLT) public health workers found that 52.8% of respondents experienced symptoms of at least one of the following mental health conditions: depression, anxiety, or posttraumatic stress disorder (PTSD) (4); however, more recent estimates of mental health symptoms among this population are limited. To evaluate trends in these conditions from the previous year, the prevalence of symptoms of mental health conditions and suicidal ideation, a convenience sample of STLT public health workers was surveyed during March 14-25, 2022. In total, 26,069 STLT public health workers responded to the survey. Among respondents,† 6,090 (27.7%) reported symptoms of depression, 6,467 (27.9%) anxiety, 6,324 (28.4%) PTSD, and 1,853 (8.1%) suicidal ideation. Although the prevalences of depression, anxiety, and PTSD among public health workers were lower (p<0.001)§ among 2022 survey respondents compared with those of 2021 survey respondents (4), the prevalences of symptoms of suicidal ideation, anxiety, depression, and PTSD remained high among those who worked >60 hours per week (range = 11.3%-45.9%) and those who spent ≥76% of their work time on COVID-19 response activities (range = 9.0%-37.6%). Respondents were less likely to report mental health symptoms if they could take time off (prevalence ratio [PR] range = 0.48-0.55), or if they perceived an increase in mental health resources from their employer (PR range = 0.58-0.84). To support the mental health of public health workers, public health agencies can modify work-related factors, including making organizational changes for emergency responses and facilitating access to mental health resources and services.¶.
COVID-19 follow-up programmes across Europe: an ERS END-COVID CRC survey
Authors: Claudia Valenzuela, Mattia Nigro, James D. Chalmers, Scott Wagers, Avinash Aujayeb, Merel E. Hellemons, Judith Löffler-Ragg, Christopher E. Brightling, Stefano Aliberti
Journal: European Respiratory Journal (2022)

SARS-CoV-2 is responsible for a multi-organ syndrome that can last over 12 months after the initial infection, including pulmonary and systemic consequences with residual radiological or functional alterations [1–3]. According to international guidelines, post-COVID-19 syndrome or condition is defined by a variety of signs and symptoms occurring during or after an infection consistent with COVID-19, lasting for more than 8–12 weeks and not explained by an alternative diagnosis [4, 5]. Main symptoms are fatigue, dyspnea, arthralgia, chest pain, cough and neurocognitive impairment [6]. Approximately one third of patients reported an impaired quality of life 3 months after a COVID-19 diagnosis [7]. Given the wide range of symptoms and severity reported, no set of investigations and tests seems to be suitable for everyone and the optimal follow-up after severe COVID-19 infection is still unclear, with scarce data published on this topic [4, 8, 9]. Furthermore, criteria for patients' inclusion in COVID-19 follow-up programs and standard operating procedures (SOPs) including imaging and functional assessment, telemedicine availability and characterization of the involved multidisciplinary teams across Europe are unknown. Based on published reports it can be expected that approaches to follow-up will be heterogenous among European countries [10].
The mitochondrial unfolded protein response (UPRmt): shielding against toxicity to mitochondria in cancer
Authors: Joseph R. Inigo, Dhyan Chandra
Journal: Journal of Hematology & Oncology (2022)

Abstract Mitochondria are essential for tumor growth and progression. However, the heavy demand for mitochondrial activity in cancer leads to increased production of mitochondrial reactive oxygen species (mtROS), accumulation of mutations in mitochondrial DNA, and development of mitochondrial dysfunction. If left unchecked, excessive mtROS can damage and unfold proteins in the mitochondria to an extent that becomes lethal to the tumor. Cellular systems have evolved to combat mtROS and alleviate mitochondrial stress through a quality control mechanism called the mitochondrial unfolded protein response (UPR mt ). The UPR mt system is composed of chaperones and proteases, which promote protein folding or eliminate mitochondrial proteins damaged by mtROS, respectively. UPR mt is conserved and activated in cancer in response to mitochondrial stress to maintain mitochondrial integrity and support tumor growth. In this review, we discuss how mitochondria become dysfunctional in cancer and highlight the tumor-promoting functions of key components of the UPR mt .
The molecular pathophysiology of depression and the new therapeutics
Authors: Haihua Tian, Zhenyu Hu, Jia Xu, Chuang Wang
Journal: MedComm (2022)

Major depressive disorder (MDD) is a highly prevalent and disabling disorder. Despite the many hypotheses proposed to understand the molecular pathophysiology of depression, it is still unclear. Current treatments for depression are inadequate for many individuals, because of limited effectiveness, delayed efficacy (usually two weeks), and side effects. Consequently, novel drugs with increased speed of action and effectiveness are required. Ketamine has shown to have rapid, reliable, and long-lasting antidepressant effects in treatment-resistant MDD patients and represent a breakthrough therapy for patients with MDD; however, concerns regarding its efficacy, potential misuse, and side effects remain. In this review, we aimed to summarize molecular mechanisms and pharmacological treatments for depression. We focused on the fast antidepressant treatment and clarified the safety, tolerability, and efficacy of ketamine and its metabolites for the MDD treatment, along with a review of the potential pharmacological mechanisms, research challenges, and future clinical prospects.
MARCKSL1–2 reverses docetaxel-resistance of lung adenocarcinoma cells by recruiting SUZ12 to suppress HDAC1 and elevate miR-200b
Authors: Min Jiang, Feng Qi, Kai Zhang, Xiaofei Zhang, Jingjing Ma, Suhua Xia, Longbang Chen, Zhengyuan Yu, Jing Chen, Dongqin Chen
Journal: Molecular Cancer (2022)

Abstract Background Long non-coding RNAs (lncRNAs) are implicated in the development of multiple cancers. In our previous study, we demonstrated that HDAC1/4-mediated silencing of microRNA-200b (miR-200b) enhances docetaxel (DTX)-resistance of human lung adenocarcinoma (LAD) cells. Methods and results Herein, we probed the function of LncRNA MARCKSL1–2 (MARCKSL1-transcript variant 2, NR_052852.1) in DTX resistance of LAD cells. It was found that MARCKSL1–2 expression was markedly reduced in DTX-resistant LAD cells. Through gain- or loss- of function assays, colony formation assay, EdU assay, TUNEL assay, and flow cytometry analysis, we found that MARCKSL1–2 suppressed the growth and DTX resistance of both parental and DTX-resistant LAD cells. Moreover, we found that MARCKSL1–2 functioned in LAD through increasing miR-200b expression and repressing HDAC1. Mechanistically, MARCKSL1–2 recruited the suppressor of zeste 12 (SUZ12) to the promoter of histone deacetylase 1 (HDAC1) to strengthen histone H3 lysine 27 trimethylation (H3K27me3) of HDAC1 promoter, thereby reducing HDAC1 expression. MARCKSL1–2 up-regulated miR-200b by blocking the suppressive effect of HDAC1 on the histone acetylation modification at miR-200b promoter. Furthermore, in vivo analysis using mouse xenograft tumor model supported that overexpression of MARCKSL1–2 attenuated the DTX resistance in LAD tumors. Conclusions We confirmed that MARCKSL1–2 alleviated DTX resistance in LAD cells by abolishing the inhibitory effect of HDAC1 on miR-200b via the recruitment of SUZ12. MARCKSL1–2 could be a promising target to improve the chemotherapy of LAD. Graphical abstract
hUC-EVs-ATO reduce the severity of acute GVHD by resetting inflammatory macrophages toward the M2 phenotype
Authors: Yan Su, Xueyan Sun, Xiao Liu, Qingyuan Qu, Liping Yang, Qi Chen, Fengqi Liu, Yueying Li, Qianfei Wang, Bo Huang, Xiao-Jun Huang, Xiao-Hui Zhang
Journal: Journal of Hematology & Oncology (2022)

Abstract Background Both extracellular vesicles from mesenchymal stromal cell-derived human umbilical cords (hUC-EVs) and arsenic trioxides (ATOs) have been demonstrated to treat acute graft-versus-host disease (aGVHD) via immunomodulation. Apart from immunomodulation, hUC-EVs have a unique function of drug delivery, which has been proposed to enhance their efficacy. In this study, we first prepared ATO-loaded hUC-EVs (hUC-EVs-ATO) to investigate the therapeutic effect and potential mechanisms of hUC-EVs-ATO in a mouse model of aGVHD after allogeneic hematopoietic stem cell transplantation (HSCT). Methods An aGVHD model was established to observe the therapeutic effects of hUC-EVs-ATO on aGVHD. Target organs were harvested for histopathological analysis on day 14 after transplantation. The effects of hUC-EVs-ATO on alloreactive CD4 + were evaluated by flow cytometry in vivo and in vitro. Flow cytometry, RT-PCR, immunofluorescence colocalization analysis and Western blot (Wb) analysis were performed to examine macrophage polarization after hUC-EV-ATO treatment. The cytokines in serum were measured by a cytometric bead array (CBA). TEM, confocal microscopy and Wb were performed to observe the level of autophagy in macrophages. A graft-versus-lymphoma (GVL) mouse model was established to observe the role of hUC-EVs-ATO in the GVL effect. Results The clinical manifestations and histological scores of aGVHD in the hUC-EVs-ATO group were significantly reduced compared with those in the ATO and hUC-EVs groups. The mice receiving hUC-EVs-ATO lived longer than the control mice. Notably, hUC-EVs-ATO interfering with alloreactive CD4 + T cells differentiation were observed in aGVHD mice but not in an in vitro culture system. Additional studies showed that depletion of macrophages blocked the therapeutic effects of hUC-EVs-ATO on aGVHD. Mechanistically, hUC-EVs-ATO induced autophagic flux by inhibiting mammalian target of rapamycin (mTOR) activity to repolarize M1 to M2 macrophages. Additionally, using a murine model of GVL effects, hUC-EVs-ATO were found not only to reduce the severity of aGVHD but also to preserve the GVL effects. Taken together, hUC-EVs-ATO may be promising candidates for aGVHD treatment. Conclusions hUC-EVs-ATO enhanced the alleviation of aGVHD severity in mice compared with ATO and hUC-EVs without weakening GVL activity. hUC-EVs-ATO promoted M1 to M2 polarization via the mTOR-autophagy pathway. hUC-EVs-ATO could be a potential therapeutic approach in aGVHD after allo-HSCT.
Comparison of Outcomes of Ischemic Stroke Initially Imaged With Cranial Computed Tomography Alone vs Computed Tomography Plus Magnetic Resonance Imaging
Authors: Heitor Cabral Frade, Susan E. Wilson, Anne Beckwith, William J. Powers
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Patients with acute ischemic stroke often undergo magnetic resonance imaging (MRI) in addition to computed tomography (CT), but its association with clinical outcomes is uncertain. <h3>Objective</h3> To assess whether clinical outcomes of patients with acute ischemic stroke with initial CT alone were noninferior to those with additional MRI. <h3>Design, Setting, and Participants</h3> A retrospective observational propensity score–matched cohort study of clinical outcomes at discharge and 1 year for patients hospitalized with acute ischemic stroke was conducted at an academic medical center between January 2015 and December 2017. Data collection from an electronic medical record system performed from May 2020 through January 2022 was not completely blinded. Noninferiority margins were based on the designs of previous randomized clinical trials of ischemic stroke treatments. Statistical analysis was performed in January 2022. Participants were adults hospitalized with acute ischemic stroke with admission diagnosis based on CT. Exclusion criteria were primarily missing data. From 508 eligible patients, all 123 cases with additional MRI were propensity-score matched to 123 controls without. <h3>Exposure</h3> MRI after initial diagnosis. <h3>Main Outcomes and Measures</h3> Death or dependence at hospital discharge (modified Rankin Scale score of 3-6) and stroke or death occurring in survivors within 1 year after discharge. <h3>Results</h3> Among 246 participants, the median age was 68 years (IQR, 58-78.8 years) and 131 (53.0%) were men. Death or dependence at discharge occurred more often in patients with additional MRI (59 of 123 [48.0%]) than in those with CT alone (52 of 123 [42.3%]; absolute difference, 5.7%; 95% CI, −6.7% to 18.1%), meeting the −7.50% criterion for noninferiority. Stroke or death within 1 year after discharge determined for 225 of 235 (96%) survivors occurred more often in patients with additional MRI (22 of 113 [19.5%]) than in those with CT alone (14 of 112 [12.5%]; relative risk, 1.14; 95% CI, 0.86-1.50), meeting the 0.725 relative risk criterion for noninferiority. <h3>Conclusions and Relevance</h3> This propensity score–matched cohort study of patients hospitalized with acute ischemic stroke found that a diagnostic imaging strategy of initial CT alone was noninferior to initial CT plus additional MRI with regard to clinical outcomes at discharge and at 1 year. Further research is needed to determine which patients hospitalized with acute ischemic stroke benefit from MRI.
The Challenges of HLA Class I Loss in Cancer Immunotherapy: Facts and Hopes
Authors: Natalia Aptsiauri, Federico Garrido
Journal: Clinical Cancer Research (2022)

HLA class I molecules are key in tumor recognition and T cell-mediated elimination. Loss of tumor HLA class I expression with different underlying molecular defects results in reduced antigen presentation and facilitates cancer immune evasion. It is also linked to significant changes in tumor microenvironment and tissue architecture. In this review, we summarize the current advances and future perspectives in the understanding of the mechanisms of MHC/HLA class I alterations during the natural history of tumor progression from a primary lesion to distant metastases. We also focus on recent clinical and experimental data demonstrating that lack of response to cancer immunotherapy frequently depends on the molecular nature of tumor HLA class I aberrations. Finally, we highlight the relevance of detecting and correcting the absence of tumor HLA expression to improve immunotherapy protocols.
Novel Quadruplets and the Age of Immunotherapies in the Treatment of Newly Diagnosed Multiple Myeloma
Authors: Dickran Kazandjian, Ola Landgren
Journal: JAMA Oncology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
HPV DNA as a Biomarker in Oropharyngeal Cancer: A Step in the Right Direction
Authors: A. Dimitrios Colevas
Journal: Clinical Cancer Research (2022)

Summary Lack of prospectively planned follow-up and minimal characterization of the patient population studied complicate interpretation of circulating human papillomavirus (HPV) DNA as a prognostic biomarker for patients with HPV-associated oropharyngeal carcinoma treated with curative intent. See related article by Berger et al., p. 4292
Elotuzumab and Weekly Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Without Transplant Intent
Authors: Benjamin A. Derman, Ankit Kansagra, Jeffrey Zonder, Andrew T. Stefka, David L. Grinblatt, Larry D. Anderson, Sandeep Gurbuxani, Sunil Narula, Shayan Rayani, Ajay Major, Andrew Kin, Ken Jiang, Theodore Karrison, Jagoda Jasielec, Andrzej J. Jakubowiak
Journal: JAMA Oncology (2022)

Treatment of newly diagnosed multiple myeloma (NDMM) with a quadruplet regimen consisting of a monoclonal antibody, proteasome inhibitor, immunomodulatory imide, and corticosteroid has been associated with improved progression-free survival (PFS) compared with triplet regimens. The optimal quadruplet combination, and whether this obviates the need for frontline autologous stem cell transplant (ASCT), remains unknown. We evaluated elotuzumab and weekly carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) without ASCT in NDMM.To investigate the efficacy of Elo-KRd using a measurable residual disease (MRD)-adapted design in NDMM regardless of ASCT eligibility.This multicenter, single-arm, phase 2 study enrolled patients between July 2017 and February 2021. Median follow-up was 29 months.Twelve to 24 cycles of Elo-KRd; consecutive MRD-negative results at 10-6 by next-generation sequencing (NGS) after cycles 8 (C8) and 12 determined the duration of Elo-KRd. This was followed by Elo-Rd (no carfilzomib) maintenance therapy until disease progression.The primary end point was the rate of stringent complete response (sCR) and/or MRD-negativity (10-5) after C8 Elo-KRd. Secondary end points included safety, rate of response, MRD status, PFS, and overall survival (OS). As an exploratory analysis, MRD was assessed using liquid chromatography mass spectrometry (MS) on peripheral blood samples.Forty-six patients were enrolled (median age 62 years, 11 [24%] aged >70 years). Overall, 32 (70%) were White, 6 (13%) were Black, 3 (6%) were more than 1 race, and 5 (11%) were of unknown race. Thirty-three (72%) were men and 13 (28%) were women. High-risk cytogenetic abnormalities were present in 22 (48%) patients. The rate of sCR and/or MRD-negativity after C8 was 26 of 45 (58%), meeting the predefined statistical threshold for efficacy. Responses deepened over time, with the MRD-negativity (10-5) rate increasing to 70% and MS-negativity rate increasing to 65%; concordance between MRD by NGS and MS increased over time. The most common (>10%) grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively). There was 1 grade 5 myocardial infarction. The estimated 3-year PFS was 72% overall and 92% for patients with MRD-negativity (10-5) at C8.An MRD-adapted design using elotuzumab and weekly KRd without ASCT showed a high rate of sCR and/or MRD-negativity and durable responses. This approach provides support for further evaluation of MRD-guided deescalation of therapy to decrease treatment exposure while sustaining deep responses.ClinicalTrials.gov Identifier: NCT02969837.
Incidence of Anaplastic Large-Cell Lymphoma of the Breast in the US, 2000 to 2018
Authors: Connor J. Kinslow, Arreum Kim, Gloria I. Sanchez, Simon K. Cheng, Lisa A. Kachnic, Alfred I. Neugut, David P. Horowitz
Journal: JAMA Oncology (2022)

This cohort study of data from the Surveillance, Epidemiology, and End Results 18 database examines the incidence of anaplastic large-cell lymphoma of the breast in the US from 2000 to 2018.
Antibody Titers After a Third and Fourth SARS-CoV-2 BNT162b2 Vaccine Dose in Older Adults
Authors: Noa Eliakim-Raz, Amos Stemmer, Nassem Ghantous, Asaf Ness, Muhammad Awwad, Yaara Leibovici-Weisman, Salomon M. Stemmer
Journal: JAMA Network Open (2022)

This cohort study evaluates the response to a third and fourth SARS-CoV-2 BNT162b2 vaccine dose among individuals aged 60 years or older by evaluating antispike immunoglobulin G antibody titers before and after each dose.